In skin wounds, angiogenesis is characterized by the abundant growth of new capillaries, ultimately creating a vascular bed that is several times denser than normal tissue. As the wound resolves, most of these excess vessels are removed, and the vascular content returns to a near normal state. While it has long been assumed that a high level of capillary growth is essential for optimal healing, recent studies by us and others challenge that notion. Our data suggests that normally healing wounds exhibit an overly robust and largely dysfunctional angiogenic response that has detrimental effects on repair outcomes. Our work demonstrates that pharmacologic treatments that establish a more refined and immediately functional vasculature improve healing and reduce scar formation. A possible mechanism by which the normally vigorous angiogenic response might spur scarring and fibrosis in wounds is via apoptotic endothelial cells. During wound resolution, a substantial apoptotic endothelial cell load is created when capillaries are pruned back to normal levels. Our preliminary data shows that apoptotic endothelial cells (EC) can directly influence fibroblast function, thereby connecting vascular overgrowth, vascular regression, EC apoptotic load, and scar formation. The central concept that underpins this application is that pharmacologic treatments that force the rapid development of a mature vasculature support ideal healing, in part by reducing the apoptotic EC load. Aim 1 will advance toward clinical trials by a) assessing the effect of a pharmacologic reduction of angiogenesis in a clinically relevant rabbit model of hypertrophic scar formation, and b) surveying vascular content and maturity in human scar tissues. Aims 2 and 3 address the central hypothesis that apoptotic EC directly influence wound resolution and outcomes. Aim 2 will identify factors produced by apoptotic EC that provoke wound fibrosis. Aim 3 will examine how apoptotic EC are cleared from wounds, and will establish how engulfment of apoptotic EC bodies affects wound resolution. The proposed work is innovative because it addresses the unique clinical approach of down-regulating the angiogenic response in wounds to reduce scar formation. Further innovation comes from the examination of the influence of apoptotic EC, as the effect of the considerable endothelial apoptotic load that occurs during wound resolution is almost entirely unstudied. The significance of this research lies in the potential application to the clinical problems of hypertrophic scars and other fibrotic diseases. The findings will support our long term goal of understanding the regulation of wound angiogenesis in health and disease, and of capitalizing upon this knowledge to improve wound healing outcomes.